1. Field of the Invention
The present invention relates to novel uses of adipic acid, in particular, a method for preventing or treating obesity, diabetes, dyslipidemia, non-alcoholic fatty liver or insulin resistance syndrome.
2. Background of Technique
At present, 1.7 billion people amounting to about 25% of the world population are overweight (BMI>25) and more than 300 million people including 120 million in the US, Europe and Japan are classified as obese (BMI>30). Among the OECD countries, the US has the highest obesity rate of 31% of population, followed by Mexico (24%), England (23%), Greece (22%), Australia (22%), New Zealand (21%), Hungary (19%), Canada (14%), Spain (13%), Ireland (13%), Germany (13%), Portugal (13%), Finland (13%), Turkey (12%) and Belgium (12%). The number of obese people in China is 70 million and the body weight control-related market is expanding, estimated at about 10 billion yuan. Childhood obesity is also increasing rapidly worldwide, with 1 in 5 children being obese. As such, childhood obesity is becoming a serious social issue. Since childhood obesity is the main cause of the life style diseases including diabetes, hypertension, stroke, etc. with increased blood cholesterol and triglyceride level, 80% or more of obese children are likely to become obese adults. Further, since increased fat stimulates secretion of sex hormones and induces early adolescence, childhood obesity may cause growth problems. Also, it negatively affects blood circulation and nourishment.
According to statistics of Korea Institute for Health and Social Affairs, the socioeconomic loss caused by obesity and obesity-related complications in 2006 is estimated at 2.1 trillion won including medical cost and indirect cost such as loss of earning. Thus, in 2010, the Korean government has decided to reduce the obesity rate down to 20% in adults and to 15% in youth, and is exploring ways to accurately define and diagnose obesity and metabolic diseases. To strategies for achieving objective, the government has been looking for the exact definition and measuring method about obesity and metabolic diseases.
Obesity drugs that are marketed inside and outside Korea include ‘Xenical’ (Roche Korea) with orlistat as main ingredient and approved by the FDA, ‘Reductil’ (Ilsung Pharmaceuticals) with sibutramine as main ingredient, ‘Exolise’ (Guju Pharma) with green tea catechol as main ingredient, or the like. Xenical, which reduces absorption of fat by inhibiting lipase, has the gastrointestinal-related side effects such as steatorrhea, gas generation and reduced absorption of oil-soluble vitamins. Reductil, which increases serotonin and noradrenaline levels in the sympathetic nervous system, has side effects such as headache, dry mouth, loss of appetite, insomnia, constipation, etc. Besides, a large number of anti-obesity drugs have been withdrawn from the market due to severe side effects. For example, aminophylline is reported to have various side effects in the nervous, circulatory and digestive systems despite its excellent effect of reducing body fat. Also, fenfluramine, dexfenfluramine, topiramate, ephedrine, etc. have been banned from being marketed as obesity drugs. As the synthetic drugs show limitations in side effects and in overcoming chronic diseases, foods and drugs derived from natural sources are drawing attentions.
NAFLD (non-alcoholic fatty liver disease) refers to a liver disease associated with triglyceride accumulation in the liver regardless of drinking alcohols, including steatosis and NASH (non-alcoholic steatohepatitis). Steatosis is considered benign diseases with good prognosis in clinic, but NASH accompanied with fatty liver, inflammation or fibrosis is recognized as progressive liver diseases inducing cirrhosis or liver cancer.
The obesity and the insulin resistance are representative of risk factors for NAFLD. The risk factors of hepatic fibrosis progression are, for example, obesity (BMI>30), ratio of liver function parameters detected in serum (AST/ALT>1) and diabetes. Hepatitis C carriers having the non-alcoholic fatty liver would be progressed to liver cancer; and therefore there are emerging needs for prevention and treatment of non-alcoholic fatty liver. 69-100% of patients with non-alcoholic fatty liver have obesity and 20-40% of patients in obesity are accompanied with fatty liver. Especially, prevalence of liver disease in the male obesity patients is higher than obesity women patients. There has been reported that 3-30% of adults with normal weight as well as obesity patients have fatty liver diseases in the Western society. In Japan having similar diet patterns to Korea, the prevalence of non-alcoholic fatty liver is estimated to be approximately 20% and 1% of them is estimated to be NASH. Non-alcoholic fatty liver became problems in obese children as well as adults. 10-77% of obese children (inhabited in Europe, USA and Asia) show non-alcoholic fatty liver lesions, because the most important risk factor for non-alcoholic liver disease is obesity.
The pathogenesis of non-alcoholic fatty liver may be explained by two mechanisms. The first mechanism is that the increase in free fatty acids inhibits fatty acid oxidation in hepatocytes, thereby accumulating fatty acids in hepatocytes to cause non-alcoholic fatty liver. The second mechanism involves a variety of physiological factors associated with inflammation and fibrosis progression. More specifically, the increase in levels of fatty acid induces to elevate the expression of cytochrome peroxidase 2E1 and CYP2E1 and to generate reactive oxygen species resulting in lipid peroxidation of liver cell membrane and the increase in LPS and oxidative stress, increasing the level of TNF-α being responsible for apoptosis of hepatocytes, finally inducing liver damage. The insulin resistance and the accumulation of fatty acids contribute to mitochondrial dysfunction, and the latter increases reactive oxygen species and nitric oxide synthase (NOS), thereby inducing cell death.
The best way to treat NAFDL may be considered a weight loss through lifestyle changes (e.g., the exercise). However, when it is difficult to treat NAFDL with only exercise, chemotherapeutics may be combined with exercise. Chemotherapeutics for non alcoholic fatty liver are classified: First, there are drugs with remediation of risk factors for treating and improving fatty liver, including obesity drugs (e.g., orlistat), insulin resistance drugs (e.g., metformin, pioglitazone and rosiglitazone), and hyperlipidemia drugs (e.g., clofibrate, gemfibrozil, bezafibrate, atorvastatin and simvastatin). Metformin increases oxidation of fatty acids, decreases lipogenic enzymes and improves hyperinsulinism and insulin resistance. Meanwhile, thiazolidinedione, rosiglitazone and pioglitazone are capable of activating PPARγ as nuclear hormone receptors to promote the glucose uptake in muscles. Secondly, there are drugs with potentials to recover liver cell damage being independent on remediation of risk factors of non-alcoholic fatty liver, including hepatocyte protectors (e.g., ursodeoxycholoc acid and taurine), antioxidants (e.g., Vitamins E and C), and nutritional supplements (e.g., lecithin, betaine, and N-acetylcysteine). Unfortunately, there are no more plausible drugs with excellent therapeutic effects without adverse effects.
Adipic acid contained in sugar beet, beetroot and gambir is carboxylic acid compound, which is called as 1,4-butanedicarboxylic acid, 1,6-hexanedioic acid, acifloctin, acinetten, adipinic acid, hexanedioic acid, octafluorohexanedioic acid or molten adipic acid. Adipic acid has the molecular formula of C6H10O4 and a molecular weight of 146.1 g/mol, represented by the following chemical formula:

Adipic acid has been registered as “acidity regulator” in the food additives database of Domestic Food Code. It is also registered as acidity regulator in the Food and Color Additive Database of the U.S. FDA. In addition, it has been also reported to have anti-ketogenic effect and anti-hypertensive effect. In the rat, adipic acid is known to be effective for improving ketosis caused by long-chain (long-chain) and short-chain monocarboxylic acids (Mortensen P B, Biochim Biophys Acta 664: 335˜48, (1981)). Furthermore, a clinical study conducted in South Korea revealed that patients treated with amlodipine adipate for 8 weeks exhibited alleviated symptoms of hypertension (Lee H Y. Et al, Clinical Therapeutics., 27728-739, (2005)).
Adipic acid is an edible substance with a significant high safety. It is noteworthy that the reported LD50 of adipic acid is more than 11,000 mg/kg (rats) and 4,175 mg/kg (mice), respectively (Kennedy G L Jr, Drug Chem Toxicol. 25 (2):191-202, (2002)).
Throughout the specification, a number of publications and patent documents are referred to and cited. The disclosure of the cited publications and patent documents is incorporated herein by reference in its entirety to more clearly describe the state of the related art and the present disclosure.